Research Highlights from Padmaja Genesh - March 2021
Non-invasive Genetic Risk Test for Alzheimer’s Coming to EU, US
Early detection of possible risk for this progressive, degenerative disease could encourage lifestyle changes that might slow Alzheimer’s onset and the rate of cognitive loss.
The test has received the CE mark in Europe – approval that it meets pre-established safety, health, and environmental protection requirements – and it will also be available in the U.S. by the end of June, the company announced.
The risk of developing Alzheimer’s is influenced by genetic factors and by lifestyle factors – such as hypertension, diabetes, smoking, physical inactivity etc. which contributes to 30% of the overall risk.
Although this genetic risk remains constant, the overall risk for Alzheimer’s is thought to increase with age.
Research has shown that lifestyle changes can significantly mitigate the risk of developing Alzheimer’s disease, delay the onset of symptoms, and slow the rate of disease progression.
genoSCORE-LAB analyzes a person’s genetic information against a collection of more than 100,000 single nucleotide polymorphisms (small gene variants) that are associated with, or are protective against, Alzheimer’s disease. Based on the evaluation of the contribution of different combined genetic risk factors, it gives a measure of the overall polygenic risk score.
Cytox reports that its genoSCORE-LAB only requires a saliva or blood sample that could be collected at a clinic, or through a mouth swab done at home. It can only be ordered by a physician, and costs are not covered by public healthcare plans or private insurers at this time.
However, the company notes that test findings are not conclusive, and constitute only a measure of relative risk of possible disease onset. A high test result does not indicate a person will develop Alzheimer’s, and a low result does not mean a person will not develop it.
At present, the test is validated for use solely with people of European ancestry. Physicians can register and order a genoSCORE-LAB test at a patient’s request, should they agree to the test, through the company’s website. Results are returned to the ordering physician.
Neurostimulation Slows Decline in Mild-to-moderate Alzheimer’s, Trial Finds
Non-invasive neurostimulation given to people with mild-to-moderate Alzheimer’s disease significantly and safely slowed their rate of functional and cognitive decline, meeting key goals of the Phase 2 OVERTURE study, according to data presented at the 2021 AD/PD Conference.
Its neurostimulation device, being referred to as a digital therapeutic, uses gamma frequency technology for neuromodulation. With this system, a patient’s brainwave patterns are analyzed to design an individualized sequence of visual or auditory signals meant to provoke certain therapeutic neural activity.
Cognito Therapeutics is the maker of this device.
Patients were randomized to either 40 hertz (Hz) of gamma frequency neuromodulation or a sham stimulation (placebo), given at the home for one hour each day for six months.
Changes in functional abilities from baseline, and changes in cognitive decline via the Mini-Mental State Examination (MMSE) were evaluated for participants with this disease. Brain atrophy and changes in brain volume were also measured using magnetic resonance imaging, taken once at the study’s start and again after six months of treatment.
Cognito reports that 33 Alzheimer’s patients given gamma frequency neuromodulation showed an 84% slowing of functional decline and an 83% slowing in memory and cognitive decline relative to 20 patients on sham stimulation. Thirty treated patients also demonstrated a 61% reduction in brain atrophy and volume loss compared to 19 people in the sham group.
The company interpreted the decline in atrophy and volume loss as evidence of a potential disease-modifying effect, meaning that the treatment may act on Alzheimer’s underlying disease mechanisms.
Pivotal Phase 3 Trials of Oral Simufilam Planned for Year’s End
Cassava Sciences plans to launch two Phase 3 clinical trials evaluating the efficacy of Simufilam, its investigational oral treatment for Alzheimer’s disease, in the second half of this year, the company announced.
If successful, results of these studies in patients with mild-to-moderate disease will support a request for Simufilam’s approval.
Simufilam, previously called PTI-125, is a small oral molecule designed to restore the normal shape and function of filamin A (FLNA), a protein that is misfolded in people with Alzheimer’s and believed to play a role in the accumulation of toxic protein clumps (aggregates) within nerve cells.
Top-line data from a previous Phase 2b trial (NCT04079803) in more than 60 people with mild to moderate Alzheimer’s showed that treatment with Simufilam safely lowered levels of biomarkers of disease activity, neurodegeneration, and inflammation.
FDA officials agreed that findings from these Phase 3 trials, in combination with previous trial data, would be sufficient to show evidence of clinical efficacy for Simufilam as an Alzheimer’s treatment.
One Phase 3 trial will determine whether Simufilam slows the rate of decline in patients’ cognition and their ability to go about daily life activities, compared with a placebo.
It will enroll about 1,000 people with mild-to-moderate Alzheimer’s, who will be randomized to treatment with one of two doses of the investigational medication (50 or 100 mg), or to a placebo, taken by mouth twice daily for 18 months. Plans are to initiate this trial between July and September.
The other Phase 3 study will evaluate changes in symptoms — specifically, whether Simufilam treatment improves cognition and participation in daily life activities, again relative to a placebo.
This trial will enroll approximately 600 mild-to-moderate Alzheimer’s patients, who will be randomized to treatment with Simufilam (at a dose of 100 mg) or to a placebo, taken twice daily by mouth, for nine months to a year. The company plans to initiate this trial between October and the close of December.
Both trials will use the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) as co-primary endpoints (their main efficacy measures). ADAS-Cog measures cognition, while ADCS-ADL assesses overall abilities in such everyday tasks as dressing yourself, preparing meals, watching TV, or engaging in conversations.
The Integrated Alzheimer’s Disease Rating Scale (iADRS) — a clinical tool that combines cognitive and functional scores from ADAS-Cog and ADCS-ADL — will be assessed as a secondary endpoint. Other secondary endpoints in both trials include levels of Alzheimer’s-associated biomarkers, as well as the Neuropsychiatric Inventory (NPI), used to evaluate the presence and severity of dementia-related behavior.
Salbutamol, for Respiratory Ills, Seen to Improve Blood Flow in Brain
Use of salbutamol significantly improved blood flow — a measure of cerebral perfusion, or the steady flow of nutrients and oxygen via the blood to brain tissue — in healthy people in a Phase 1 trial, according to data from CuraSen Therapeutics, the investigative therapy’s developer. These results were presented at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases, held virtually on March 9–14.
Poor cerebral perfusion is associated with cognitive decline and diminished neuronal activity, and is considered an early sign of Alzheimer’s disease.
Salbutamol, also known as albuterol, is an inhalation therapy for respiratory diseases like asthma, bronchitis, and emphysema. It is a short-acting bronchodilator that works by relaxing and opening the airways to the lungs, making breathing easier.
The therapy is a selective beta2-adrenergic receptor agonist — compounds that bind to a receptor and activate it, mimicking a biological response. These receptors are present both on the smooth muscle of the bronchi and in the brain.
CuraSen’s early trial evaluated the effects of three doses of salbutamol (0.3, 0.9 and 1.8 mg), as an IV infusion, on cerebral perfusion — the blood pressure gradient that directly influences blood flow in the brain — in 12 healthy volunteers.
Participants who received the highest dose of salbutamol were also given nadolol, a beta blocker used to treat hypertension, to counter associated Salbutamol side effects such as tremor, high heart rate, high blood sugar (hyperglycemia), or low potassium levels (hypokalemia).
Researchers used a non-invasive technique, MRI imaging with arterial spin labeling (ASL), to monitor brain perfusion before and after treatment.
Results showed that the highest dose of salbutamol significantly increased, by 27.4%, blood flow in the thalamic region of the brain, an area important to cognitive processes. This effect which was not observed at lower doses.
CuraSen is also evaluating other beta agonists, with potentially greater brain penetration, as potential therapies. It plans to present this early work, reported to “demonstrate a robust global increase in perfusion, as well as evidence of cognitive benefit,” at an upcoming scientific meeting.
Donanemab Shows Potential for Early Alzheimer’s in Phase 2 Trial
Donanemab showed an ability to slow cognitive decline and the loss of daily life abilities in people at earlier stages of Alzheimer’s disease relative to those given a placebo in the Phase 2 TRAILBLAZER-ALZ trial, researchers report.
Donanemab is an antibody designed to recognize, and bind to, a harmful form of the beta-amyloid protein that clumps into toxic plaques in Alzheimer’s patients, and remove them. Clearing such plaques from the brain is expected to slow Alzheimer’s progression.
The Phase 2 study (NCT03367403) evaluated Donanemab safety, tolerability, and efficacy, as compared with a placebo, in adults with early stage and symptomatic Alzheimer’s.
The trial enrolled 257 people, ages 60 to 85, and randomly assigned 131 to Donanemab and 126 to receive placebo.
Changes from baseline in the integrated Alzheimer’s Disease Rating Scale (iADRS) was the study’s primary goal. iADRS is a combined measure of cognitive and daily life abilities, used to track disease progression and detect treatment differences, such as those between patients on Donanemab and on placebo, with lower scores indicating greater cognitive and functional decline.
Over 76 weeks of treatment, iADRS scores of treated patients dropped by an average of 6.86 points, while those of the placebo group declined by 10.06 points — a difference of 3.2 points or 32%. Significant differences in the rates of decline, as measured by the iADRS, began to appear at 36 weeks, or nine months, of treatment.
Donanemab did clear amyloid plaques more effectively than placebo.
The percentage of participants classified as amyloid negative grew from 40% to 67.8% between weeks 24 and 76, compared to no significant change among those receiving placebo.
A global Phase 3 trial of Donanemab, called TRAILBLAZER-ALZ-2 (NCT04437511) is underway in this same patient group, and starting or getting ready to enroll up to 1,500 diagnosed adults at 230 sites worldwide. More information is available here.
Sargramostim, Immune System Activator, May Aid Cognition, Small Trial Finds
A team led by researchers at the University of Colorado reported the results of a Phase 2 clinical trial (NCT01409915) that evaluated the safety and efficacy of Sargramostim in a small group of 40 Alzheimer’s patients, with mild-to moderate symptoms.
This study builds on previous findings that people with rheumatoid arthritis (RA) are at a lower risk of Alzheimer’s. Although this was originally thought to result from RA patients taking certain kinds of anti-inflammatory medications, newer findings suggest this could be because certain pro-inflammatory molecules are present at higher levels in people with RA.
Specifically, prior work has suggested that a pro-inflammatory signaling molecule called granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) could protect against Alzheimer’s.
Sargramostim contains a recombinant (lab-made) version of GM-CSF. It is currently approved, under the brand name Leukine, as a treatment to boost the activity of the immune system in conditions where the immune system is impaired (e.g., some kinds of cancer).
In the trial patients were randomized to either Sargramostim (at a standard dosage of 250 micrograms/square meter/day for five days each week) or to a placebo, for a total of three weeks. Participants underwent follow-up assessments after 45 and 90 days.
About half of these patients were female, their average age was about 70, and all but one were white.
The study’s main goal was to assess the safety of Sargramostim in people with Alzheimer’s. No serious adverse events related to the treatment were reported. The most common treatment-related side effects — including headache, skin-related reactions, and digestive issues — were in line with the medication’s known safety profile.
Analyses indicated that the treatment activated the immune system as expected, evidenced by higher numbers of immune cells and by increased levels of pro-inflammatory signaling molecules called cytokines.
Though the trial was not designed to thoroughly assess efficacy, researchers highlighted that scores on the Mini‐Mental State Examination (MMSE) improved significantly, by 1.45 points on average, over three weeks in 70% of patients given Sargramostim.
Sargramostim’s use also normalized levels of Alzheimer’s-related proteins in participants’ blood. Blood levels of amyloid beta 40 — a form of amyloid beta often at low levels in people with Alzheimer’s — rose significantly with Sargramostim treatment, and were 10% higher than levels in placebo patients.
A larger trial is planned, being sponsored by the Alzheimer’s Association/Part The Cloud, the University of Colorado, the Global Down Syndrome Foundation, and the National Institute on Aging.
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